Martina Morris & Jeanette Birnbaum
To use CD4 data to increase the precision of undiagnosed estimates from the testing history model
Why
How
Impact in WA
The red line is lower when the window is longer, since the probability of infection is spread out over a longer time period.
Since 1 year is ½ of 2 years, 50% of infection probability occurs within 1 year for the 2-year window. In contrast, only 1/5 or 20% of infection probability occurs within 1 year for the 5-year window.
For never-testers, we assume a window of 18 years or age-16, whichever is smaller.
The age distribution of never-testers thus influences what window lengths they contribute to the population TID (time from infection to diagnosis).
Testing histories = Tested + Never Tested
Total N=5148
N with testing history N=3016.
Testing histories = Tested + Never Tested
MSM comprise about 2/3 of cases.
What is driving differential response rates?
50% have windows between 0 and 2 years (red plus gold).
Our assumption for never-testers almost doubles the number of windows >=5 years (blue plus purple).
58% of non-MSM have windows 5 years or longer. The 18-year assumption for never-testers is almost 4x more common among non-MSM (31%) than among MSM (7%).
Percent of cases with a concurrent AIDS diagnosis at time of HIV diagnosis, by MSM status.
Mean age at diagnosis among never-testers is 42 in non-MSM, versus 36 in MSM
Remember the assumption for never-testers: window=min(age-16,18). Cases older than 16+18=34 will all have 18-year windows.
Whether it's using BED, CD4, or concurrent AIDS dx, etc
Increasing precision will not necessarily decrease undiagnosed estimates
Total population estimates will not change greatly, but our confidence in them will increase
CD4 Unknown
| Window Length | If CD4 unknown, infection probability is mostly: |
|---|---|
| Short | Recent |
| Long | Non-recent |
CD4 Unknown
| Window Length | If CD4 unknown, infection probability is mostly: |
|---|---|
| Short | Recent |
| Long | Non-recent |
CD4 Known
| Window Length | If CD4 unknown, infection probability is mostly: | CD4=Low | CD4=High |
|---|---|---|---|
| Short | Recent | Recent (fast progressor?) | Recent |
| Long | Non-recent | Non-recent | Recent |
Those with long windows but high CD4 may be unrecognized recent infections
How to define “short” and “long”, “low” and “high”?
Years it takes for 50% of cases to reach CD4 level:
| CD4 Category | Lodi 2011 | Cori 2015 | Our approximation* |
|---|---|---|---|
| >500 | 1.3 | 2.3 | 1.5 |
| 350-500 | 4.3 | 4.2 | 4.0 |
| 200-350 | 7.9 | 8.0 | 8.0 |
| 0-200 | 11.5 | 9.0 |
* Simplified median times that are consistent with both sources. For CD4 0-200, we will retain our maximum-window assumption of 18 years. This sets a maximum median time of 9 years
Interpretation: 50% of infection probability should occur within the median time.
Implication: If a case has CD4>500 at diagnosis, for example, we expect 50% of his infection probability to occur in the 1.5 years prior to dx
Lodi S, Phillips A, Touloumi G, Geskus R, Meyer L, Thiébaut R, et al. Time from human immunodeficiency virus seroconversion to reaching CD4+ cell count thresholds <200, <350, and <500 Cells/mm3: assessment of need following changes in treatment guidelines. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011 Oct;53(8):817–25
Cori A, Pickles M, van Sighem A, Gras L, Bezemer D, Reiss P, et al. CD4+ cell dynamics in untreated HIV-1 infection: overall rates, and effects of age, viral load, sex and calendar time. AIDS Lond Engl. 2015 Nov 28;29(18):2435–46.
Base Case: 50% infection probability is in each half of the window
CD4 Case: 50% of infection probability is shifted into the CD4-based median window
| CD4 Category | CD4 Median | Impacts windows longer than |
|---|---|---|
| >500 | 1.5 | 3.0 |
| 350-500 | 4.0 | 8.0 |
| 200-350 | 8.0 | 16.0 |
Degree of impact will depend on how much longer windows are than 2x the CD4-based median
We exclude cases when their first CD4 count is not within 30 days, or if it's missing
Treatment is more likely to begin after 30 days, altering CD4 counts
High CD4s in delayed measurement groups may reflect initiation of treatment
The never-tester CD4 distribution suggests some testing in response to symptoms related to low CD4.
Never-testers with high CD4 are where the CD4 Case will have greatest impact. Never-testers with CD4 200-350 will have minimal impact.
| CD4 Category | CD4 Median | Impacts windows longer than |
|---|---|---|
| >500 | 1.5 | 3.0 |
| 350-500 | 4.0 | 8.0 |
| 200-350 | 8.0 | 16.0 |
Median time since infection = time by with 50% of infection probability has occurred
Among all cases with testing history (N=3016), average median time since infection under the Base Case and CD4 Case, and their absolute and relative differences, by MSM status.
| Base Case Median | CD4 Case Median | Absolute Difference | Percent Change | |
|---|---|---|---|---|
| MSM | 1.94 | 1.72 | -0.22 | -11.54 |
| non-MSM | 4.50 | 4.00 | -0.50 | -11.16 |
Mean decrease in median time since infection is slighly larger for MSM (3.10 years) than for non-MSM (3.01 years).
Median decrease in median time since infection is slighly larger for MSM (2.34 years) than for non-MSM (1.94 years).
MSM have a smaller proportion impacted, but impacted cases have slightly greater decreases
Proportion of impact and degree of impact of the CD4 Case. Decreases and percent change refer to the decrease in median time since infection in going from the Base Case to the CD4 Case.
| Population | Proportion Impacted | Average Decrease | Total Decrease | Percent Change |
|---|---|---|---|---|
| MSM | 0.07 | 3.10 | 0.22 | -11.3 |
| non-MSM | 0.17 | 3.01 | 0.51 | -11.3 |
Average time undiagnosed = the mean of the TID curve
Mean TID for the Base Case and CD4 Case, by MSM status
| Population | Base Case | CD4 Case | Difference | Percent Change |
|---|---|---|---|---|
| MSM | 1.83 | 1.72 | 0.11 | -6.13 |
| non-MSM | 4.38 | 4.13 | 0.25 | -5.74 |
TID actually changes by 0.39 more percentage points for MSM than non-MSM
MSM
non-MSM
| Population | Base Case | CD4 Case | Difference | Percent Change |
|---|---|---|---|---|
| Total | 1319.0 | 1247.0 | 72.0 | 5.5 |
| MSM | 604.7 | 568.4 | 36.3 | 6.0 |
| non-MSM | 714.3 | 678.2 | 36.1 | 5.1 |
Subgroup decreases closely parallel the decreases in mean undiagnosed time (6.13% for MSM and 5.74% for non-MSM)
| Population | Base Case | CD4 Case | Absolute Difference | Percent Change |
|---|---|---|---|---|
| Total | 9.4 | 8.9 | 0.5 | 5.3 |
| MSM | 6.2 | 5.8 | 0.4 | 6.5 |
| non-MSM | 17.1 | 16.4 | 0.7 | 4.0 |
The fractions take into account diagnosed PLWH. Since the Base Case undiagnosed fraction is much higher for non-MSM, it is less sensitive than the MSM fraction to the CD4 Case's decrease of about 36 undiagnosed cases.
| Window Length | If CD4 unknown, infection probability is mostly: | CD4=Low | CD4=High |
|---|---|---|---|
| Short | Recent | Recent (fast progressor?) | Recent |
| Long | Non-recent | Non-recent | Recent |
In WA, only 10% of cases with testing history had infection windows that indicated less probability of recent infection than indicated by their CD4 count
We expected to see greater impact in non-MSM than MSM
We prioritize testing history data
We use CD4 conservatively
CD4 in cases with missing testing history
Multiple markers